Side effects
Constipation
Like loperamide and other opioids, morphine acts on the myenteric plexus in the intestinal tract, reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily by µ-opioid receptors in the bowel. By inhibiting gastric emptying and reducing propulsive peristalsis of the intestine, morphine decreases the rate of intestinal transit. Reduction in gut secretion and increases in intestinal fluid absorption also contribute to the constipating effect. Opioids also may act on the gut indirectly through tonic gut spasms after inhibition of nitric oxide generation. This effect was shown in animals when a nitric oxide precursor, L-Arginine, reversed morphine-induced changes in gut motility.Addiction
In controlled studies comparing the physiological and subjective effects of injected heroin and morphine in iniduals formerly addicted to opiates, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with no difference in subjects’ self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness. Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioids hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids.
The “rush” of injecting morphine is the reason some people become addicted, all by itself. Morphine, heroin, and related drugs produce a “rush” and “bang” when injected intravenously, or via other routes if a blood vessel is entered and the injector does not aspirate to see if the needle is in a blood vessel (or does so on purpose when injecting IM in particular, finally pushing the plunger when they get a “register” i.e. blood steadily flowing into the syringe). The rush and bang are produced by mu and perhaps delta opioid receptors being activated in huge numbers in a very short time span; the rush is the physical sensation which is helped along by vasodilation and histamine release and the bang is the very rapid onset and increase in euphoria and some related sensations of physical origin—other methods and weaker agents like codeine can sometimes produce a (delayed) bang even when swallowed on an empty stomach with or after a potentiator, but the rush is a unique property of intravenous injection and can also be produced by drugs in other categories. Antihistamines like cyclizine and tripelennamine are sometimes mixed with morphine to increase both, a potentially dangerous practise via unsupervised injection but one used medically with oral opioid administration and under direct supervision of a doctor and nurse via the IV and SC routes in particular.
Other studies, such as the Rat Park experiments, suggest that morphine is less physically addictive than others suggest, and most studies on morphine addiction merely show that “severely distressed animals, like severely distressed people, will relieve their distress pharmacologically if they can.” In these studies, rats with a morphine “addiction” overcome their addiction themselves when placed in decent living environments with enough space, good food, companionship, areas for exercise, and areas for privacy. More recent research has shown that an enriched environment may decrease morphine addiction in mice.
Morphine is a potentially highly addictive substance. It can cause psychological dependence and physical dependence as well as tolerance, with an addiction potential identical to that of heroin. When used illicitly, a very serious narcotic habit can develop in a matter of weeks, whereas iatrogenic morphine addiction rates have, according to a number of studies, remained nearly constant at one case in 150 to 200 for at least two centuries. In the presence of pain and the other disorders for which morphine is indicated, a combination of psychological and physiological factors tend to prevent true addiction from developing, although physical dependence and tolerance will develop with protracted opioid therapy. These two factors do not add up to addiction without psychological dependence which manifests primarily as a morbid seek orientation for the drug.
Tolerance
Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine.
Withdrawal
Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which unlike that of barbiturates, benzodiazepines, alcohol, or sedative-hypnotics, is not fatal by itself in neurologically healthy patients without heart or lung problems; it is in theory self-limiting in length and overall impact in that a rapid increase in metabolism and other bodily processes takes place, including shedding and replacement of the cells of many organs.
Nonetheless, suicide, heart attacks, strokes, seizures proceeding to status epilepticus, and effects of extreme dehydration do lead to fatal outcomes in a small fraction of cases.
Acute morphine and other opioid withdrawal proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes which do not reach the highest level. As commonly cited, they are:
- Stage I: Six to fourteen hours after last dose: Drug craving, anxiety
- Stage II: Fourteen to eighteen hours after last dose: Yawning, perspiration, lacrimation, crying, running nose, dysphoria, “yen sleep”
- Stage III: Sixteen to twenty-four hours after last dose: Nose running like faucet and increase in other of the above, dilated pupils, piloerection (gooseflesh), muscle twitches, hot flashes, cold flashes, aching bones & muscles, loss of appetite and the beginning of intestinal cramping.
- Stage IV: Twenty-four to thirty-six hours after last dose: Increase in all of the above including severe cramping and involuntary leg movements (“kicking the habit”), loose stool, insomnia, elevation of blood pressure, moderate elevation in body temperature, increase in frequency of breathing and tidal volume, increased pulse, restlessness, nausea
- Stage V: Thirty-six to seventy-two hours after last dose: Increase in the above, fetal position, vomiting, free and frequent liquid diarrhoea which sometimes can accelerate the time of passage of food from mouth to out of system to an hour or less, involuntary urination and ejaculation which is often painful, saturation of bedding materials with bodily fluids, weight loss of two to five kilos per 24 hours, increased WBC and other blood changes.
- Stage VI: After completion of above: Recovery of appetite (“the chucks”), and normal bowel function, beginning of transition to post-acute and chronic symptoms which are mainly psychological but which may also include increased sensitivity to pain, hypertension, colitis or other gastrointestinal afflictions related to motility, and problems with weight control in either direction.
Some authorities give the above as grades zero to four, and others add chronic withdrawal as a seventh stage. Some separate post-acute and chronic withdrawal, others do not. For an example of the use of the above system, methadone clinics require, in the absence of a direct and documented referral from a doctor, Stage II withdrawal symptoms and/or recent needle marks and/or surrender of injecting equipment and/or unused drug at the intake appointment to begin the methadone maintenance or withdrawal process; two urine tests positive for opioids must then be collected shortly thereafter.
The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually between 6–12 hours) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria, sweating and in some cases a strong drug craving. Severe headache, restlessness, irritability, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the syndrome progresses. Severe depression and vomiting are very common. During the acute withdrawal period systolic and diastolic blood pressure increase, usually beyond pre-morphine levels, and heart rate increases, which could potentially cause a heart attack, blood clot, or stroke.
Chills or cold flashes with goose bumps (“cold turkey”) alternating with flushing (hot flashes), kicking movements of the legs (“kicking the habit”) and excessive sweating are also characteristic symptoms. Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48 and 96 hours after the last dose and subside after about 8 to 12 days. Sudden withdrawal by heavily dependent users who are in poor health is very rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.
The psychological dependence associated with morphine addiction is complex and protracted. Long after the physical need for morphine has passed, the addict will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is a very long and painful process. Addicts often suffer severe depression, anxiety, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia, and other psychological disorders. The psychological dependence on morphine can, and usually does, last a lifetime. There is a high probability that relapse will occur after morphine withdrawal when neither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony to morphine’s addictive and reinforcing nature is its relapse rate. Abusers of morphine (and heroin) have one of the highest relapse rates among all drug users.
Hepatitis C
Researchers at the University of Pennsylvania have demonstrated that morphine withdrawal complicates hepatitis C by suppressing IFN-alpha-mediated immunity and enhancing virus replication. Hepatitis C virus (HCV) is common among intravenous drug users. This high association has piqued interest in determining the effects of drug abuse, specifically morphine and heroin, on progression of the disease. The discovery of such an association would impact treatment of both HCV infection and drug abuse.
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